Waelbroeck M, Camus J, Tastenoy M, Mutschler E, Strohmann C, Tacke R, Lambrecht G, Christophe J
Department of Biochemistry and Nutrition, Medical School, Free University of Brussels, Belgium.
Eur J Pharmacol. 1991 Feb 25;206(2):95-103. doi: 10.1016/0922-4106(91)90017-c.
Hexahydro-sila-difenidol and eight analogues behaved as simple competitive inhibitors of [3H]N-methyl-scopolamine binding to homogenates from human neuroblastoma NB-OK 1 cells (M1 sites), rat heart (M2 sites), rat pancreas (M3 sites), and rat striatum 'B' sites (M4 sites). Pyrrolidino- and hexamethyleneimino analogues showed the same selectivity profile as the parent compound. Hexahydro-sila-difenidol methiodide and the methiodide of p-fluoro-hexahydro-sila-difenidol had a higher affinity but a lower selectivity than the tertiary amines. Compounds containing a p-methoxy, p-chloro or p-fluoro substituent in the phenyl ring of hexahydro-sila-difenidol showed a qualitatively similar selectivity profile as the parent compound (i.e., M1 = M3 = M4 greater than M2), but up to 16-fold lower affinities. o-Methoxy-hexahydro-sila-difenidol has a lower affinity than hexahydro-sila-difenidol at the four binding sites. Its selectivity profile (M4 greater than M1, M3 greater than M2) was different from hexahydro-sila-difenidol. Replacement of the central silicon atom of hexahydro-sila-difenidol, p-fluoro-hexahydro-sila-difenidol and their quaternary (N-methylated) analogues by a carbon atom did not change their binding affinities significantly. The four muscarinic receptors showed a higher affinity for the (R)- than for the (S)-enantiomers of hexahydro-difenidol, p-fluorohexahydro-difenidol and their methiodides. The stereoselectivity varied depending on the receptor subtype and drug considered.
六氢硅二苯乙醇及其八种类似物对人神经母细胞瘤NB-OK 1细胞匀浆（M1位点）、大鼠心脏（M2位点）、大鼠胰腺（M3位点）和大鼠纹状体“B”位点（M4位点）的[3H]N-甲基东莨菪碱结合表现为简单竞争性抑制剂。吡咯烷基和六亚甲基亚氨基类似物显示出与母体化合物相同的选择性谱。六氢硅二苯乙醇甲碘化物和对氟六氢硅二苯乙醇甲碘化物比叔胺具有更高的亲和力但选择性更低。在六氢硅二苯乙醇苯环中含有对甲氧基、对氯或对氟取代基的化合物显示出与母体化合物在性质上相似的选择性谱（即M1 = M3 = M4大于M2），但亲和力低至16倍。邻甲氧基六氢硅二苯乙醇在四个结合位点的亲和力低于六氢硅二苯乙醇。其选择性谱（M4大于M1，M3大于M2）与六氢硅二苯乙醇不同。用碳原子取代六氢硅二苯乙醇、对氟六氢硅二苯乙醇及其季铵（N-甲基化）类似物的中心硅原子不会显著改变它们的结合亲和力。四种毒蕈碱受体对六氢二苯乙醇、对氟六氢二苯乙醇及其甲碘化物的（R）-对映体比对（S）-对映体具有更高的亲和力。立体选择性因所考虑的受体亚型和药物而异。
